There is an urgent need for new therapeutic drugs in many therapeutic areas. Millennium Pharmaceuticals was established to meet these challenges using fungal secondary metabolites as a major drug source. Traditionally, fungi that have been selected for drug screening are those that can be easily cultured in the laboratory; however, culturable fungi constitute only a fraction of the fungal taxa. In this project, we propose to develop a novel technology to capture the genetic diversity from unculturable fungi through genetic engineering. We will clone large segments of genomic DNA from selected unculturable fungi and introduce the cloned DNA into closely related, genetically amenable laboratory strain to express genes from the unculturable fungi and to produce novel secondary metabolites with biological activities.